Process for preparing a ((2-benzoyl-phenylcarbamoyl)methyl)-hydroxy carbamic acid ethyl ester ethyl carbonate

ABSTRACT

2-AMINO PHENYLBENZLIDENEAMINOACETIC ACID N-OXIDES ARE REACTED WITH ETHYL CHLOROFORMATE TO PRODUCE THE CORRESPONDING (2 - BENZOYLPHENYLCARBAMOY)METHYL)HYDROXYCARBAMIC ACID, ETHYL ESTER, ETHYL CARBONATE. THE PRODUCTS ARE INTERMEDIATES IN THE PREPARATION OF 1,4BENZODIAZEPINE COMPOUNDS WHICH HAVE CENTRAL NERVOUS SYSTEM ACTIVITY.

S. C. BELL March 28, 1972 PROCESS FOR PREPARING A[(Z-BENZOYLPHENYLCARBAMOYL)METHYL] HYDROXY UARBAMIC ACID, ETHYL ESTER,ETHYL CARBONATE Original Filed Feb. 18, 1956 A 7' TOR/VF Y United StatesPatent 3,652,634 PROCESS FOR PREPARING A [(Z-BENZOYL-PHENYLCARBAMOYL)METHYL]-HYDROXY CARBAMIC ACID, ETHYL ESTER, ETHYLCARBONATE Stanley C. Bell, Philadelphia, Pa., assignor to American HomeProducts Corporation, New York, N.Y. Original application Feb. 18, 1966,Ser. No. 528,623, now Patent No. 3,489,747, dated Jan. 13, 1970. DiVldedand this application June 23, 1969, Ser. No. 852,135 Int. Cl. C07c125/06 U.S. Cl. 260-463 2 Claims ABSTRACT OF THE DISCLOSURE2-amino-phenylbenzylideneaminoacetic acid N-oxides are reacted withethyl chloroformate to produce the corresponding [(2benzoylphenylcarbamoyl)methyl]hydroxycarbamic acid, ethyl ester, ethylcarbonate. The products are intermediates in the preparation of 1,4-benzodiazepine compounds which have central nervous system activity.

This application is a division of U.S. patent application Ser. No.528,623, filed Feb. 18, 1966, now U.S. Pat. No. 3,489,747.

This invention relates to compositions of matter classified in the artof chemistry as substituted 1,3-dihydro- 2H-1,4-benzodiazepin-2-ones,and to intermediates and processes for their preparation.

The invention sought to be patented in its principal composition aspectis described as residing in the concept of a chemical having a molecularstructure in which there is attached to a1,3-dihydro-5-aryl-2H-1,4-benzodiazepin-Z-one nucleus, a carbamic acidester group at the 3-position.

The tangible embodiments of the principal composition aspect of theinvention possess the inherent general physical properties of being highmelting, white crystalline solids, are substantially insoluble in water,and are solu ble in polar solvents, such as the lower aliphaticalcohols. Examination of the compounds produced according to thehereinafter described process reveals upon infrared, ultraviolet, andnuclear magnetic resonance spectrographic analysis, spectral dataconfirming the molecular structure hereiubefore set forth. Thus thecarbonyl of the ring and of the urethane linked thereto are evident. Theaforementioned physical properties taken together with the nature of thestarting materials and the mode of synthesis confirm the structure ofthe compositions sought to be patented.

The tangible embodiments of the principal aspect of the presentinvention possess the inherent applied use characteristics of exertinganti-oxytremorine and central nervous system depressant activity asevidenced by standard test procedures.

The invention sought to be patented in a second composition aspectresides in the concept of[(2-benzoylphenylcarbamonyl)methyl]hydroxycarbamic acid, ester, ethylcarbonate.

The tangible embodiments of the second composition aspect of theinvention possess the inherent general physical properties of beingwhite crystalline solids, substantially insoluble in water, and aresoluble in polar solvents such as the lower aliphatic alcohols.Examination of the compounds produced according to the hereinafterdescribed process reveals upon spectral analysis, spectral dataconfirming the molecular structure set forth. The physical propertiestaken together with the nature of the starting materials, the modes ofsyntheses in the two "ice alternate routes to the second compositionaspect presented hereinbelow and the products obtained therefrom,confirm the structure of the second compositions sought to be patented.

The tangible embodiments of the second composition aspect of theinvention possess the inherent applied use characteristics of beingintermediates for the preparation of the principal compositions of theinvention.

The invention sought to be patented in its principal process aspectresides in the concept of converting a 2-amino-a-phenylbenzylideneaminoacetic acid N-oxide to a[(Z-benzoylphenylcarbamoyl)methyl] hydroxy carbamic acid, ethyl ester,ethyl carbonate by reacting with ethyl chloroformate and cyclizing theproduct so produced with ammonia to obtain1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-3-carbamic acid, ethylester.

The invention sought to be patented in a second process aspect residesin the concept of converting a 2-hydroxyaminoacetamidobenzophenone to a[(2 benzoylphenylcarbamoyl)methyl] hydroxycarbamic acid, ethyl ester,ethyl carbonate by reacting with ethyl chloroformate and cyclizing theproduct so produced with ammonia to obtain1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin- 2-one-3-carbamic acid, ethylester.

The manner and process of making and using the invention will now begenerally described so as to enable a person skilled in the art ofchemistry to make and use the same as follows:

Referring to the drawing appended hereto, wherein the compounds areassigned Roman numerals for identification, the seqence of reactionsinvolved in the synthesis of a specific embodiment, namely7-chloro-l,3-dihydro-5- phenyl-ZH-1,4-benzodiazepin-2-one-3-carbamicacid, ethyl ester, is illustrated.

The 2-amino-a-phenylbenzylideneaminoacetic acid N- oxides(I), startingmaterials for the principal process of the invention and which areemployed for the preparation of the composition of the invention, areobtained as described in co-pending U.S. application Ser. No. 297,705,filed July 25, 1963, now abandoned. When a mixture of a2-aminox-phenylbenzylideneaminoacetic acid N-oxide and 25 ml. of ethylchloroformate in 25 ml. of a solvent, preferably chloroform, are heatedand maintained at reflux temperature for a period of about two hours,applicant has discovered that a remarkable and unusual rearrangementoccurs. The moiety attached through carbon to the l-position of phenylbecomes attached by means of the end carbon to the nitrogen atom at the2-position and the bond between the linking carbon and the head-endnitrogen is broken. A possible explanation for the unusual rearrangementis the formation of a cyclic hypothetical intermediate, as follows:

The product, so obtained, is purified by recrystallization methods knownto those skilled in the art, as for example, for a bi-solvent systemsuch as 1:1 ethylacetate/ hexane, crystallization being induced byadding more hexane, and is a [(Z-benzoylphenylcarbamoyl)methyl]hydroxycarbamic acid, ethyl ester, ethyl carbonate (HI).

Addition of this product to alcoholic ammonia followed by heatingeffects a cyclization to a 1,3-dihydro--phenyl-2H-1,4-benzodiazepin-2-one-3-carbamic acid, ethyl ester (IV).

The [(2-benzoylphenylcarbamoyl)methyl] hydroxycarbamie acid, ethylester, ethyl carbonates (I) can be prepared by reacting ethylchloroformate with a 2-hydroxyaminoacetamidobenzophenone (II). Themanner of making 2-hydroxyaminoacetamidobenzophenones used in thisalternate procedure are described in co-pending application Ser. No.301,873 filed Aug. 13, 1963, now abandoned. A mixture of the tworeactants is refluxed for about 3 hours, preferably with excess ethylchloroformate as the solvent. On removal of the solvent and triturationwith a small amount of ethanol, the desired ester, ethyl carbonate isobtained which can be cyclized as hereinbefore described to give thecorresponding 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one-3-carbamic acid, ethyl ester.

It will be apparent from the disclosure herein to those skilled in theart that for the purposes of the invention, certain of the atoms of thea-phenylbenzylideneaminoacetic acid N-oxide or thehydroxyaminoacetamidobenzophenone starting materials could besubstituted at certain positions with groups which do not interfere withthe subsequent reactions and are not themselves affected by thesubsequent reactions. Thus the phenyl of theoc-phenylbenzylideneaminoacetic acid N-oxides and the phenyl to whichthe amide nitrogen is attached to the hydroxyacetamidobenzophenones, mayin lieu of hydrogen be substituted, for example, but Without limitationthereto, with groups such as the halogens, chloro, bromo, or iodo;alkyl, methyl, ethyl or isopropyl; alkoxy, methoxy, ethoxy, orisopropoxy, at the 3, 4, 5, and 6 positions. The phenyl of thebenzylidene group of the a-phenylbenzylideneaminoacetic acid N-oxidesand the phenyl of the benzoyl group of thehydroxyacetamidobenzophenones, may similarly, in lieu of hydrogen, besubstituted, for example, but without limitation thereto, with groups atthe 2, 3, 4, 5, and 6-position such as those hereinbefore specified forthe other phenyl in the starting material molecule. Furthermore, the inlieu of the phenyl of the benzoyl grouping in thehydroxyaminoacetamidobenzophenone, heterocyclic aryl groups as, forexample, but without limitation thereto, thienyl, pyridyl, furyl, orcycloalkano, such as cyclopentyl or cyclohexyl, can be present.

It will also be present to those skilled in the art that for thepurposes of this invention, other alkyl chloroformates can besubstituted for ethyl chloroformate in the processes of the invention.Other reactive ester acid chlorides such as tosyl or mesyl can also beused in lieu thereof.

When the starting compounds are substituted as hereinbefore recited, itwill be apparent hcrefrom to those skilled in the art of chemistry, thatthe final product formed in the process of the invention will bearcorrespondingly the same substitucnts. It will be apparent that thephenyl group of the benzylidene group of thea-phenylbenzylidene-aminoacetic acid N-oxides and the phenyl to whichthe amide nitrogen is attached of the hydroxyacetamidobenzophenonebecomes the benzo group of the product S-phenylbenzodiazepin-2-0ne andthat the a-phenyl group of the a-phenylbenzylideneaminoacetic acidN-oxide and the phenyl of the benzoyl group of thehydroxyacetamidobenzophenone becomes the 5-phenyl group of the productS-phenylbenzodiazepin-2-one. Similarly whatever the group is in thealcohol group of the ester portion of the alkyl chloroformate, thisgroup will be the alcohol group of the ester in the carbamic acid esterattached to the 3-position of the product S-phenylbenzodiazepin-Z-one.Thus for the processes of the invention and for the product of theinvention produced thereby, such groups are the full equivalents of theinvention as particularly claimed.

The following examples illustrate the best mole contemplated by theinventor of using the claimed process of the invention and of the mannerof making the claimed compositions of the invention.

EXAMPLE 1 Preparation of [(Z-benzoyl 4 chlorophenylcarbamoyl)methyl]hydroxycarbamic acid, ethyl ester ethyl carbonate Refiux amixture of 4.0 g. of 5-chloro-a-phenylbenzylideneaminoacetic acidN-oxide, 25 ml. of chloroform and 25 ml. of ethyl chloroformate for 2hours. Remove the solvent under reduced presssure. Dissolve the residuein a mixture of 30 ml. of ethyl acetate and 30 ml. of hexane, filter toremove undissolved impurities. Dilute with an additional 30 m1. ofhexane. Cool and allow the solution to stand in the cold for 24 hours tocause the product to crystallize. Filter to obtain 1.9 g. of the titleproduct, M.P. 10l102.

Analysis.-Calculated for C H ClN O (percent): C, 56.20; H, 4.72; N,6.23; Cl, 7.90. Found (percent): C, 55.98; H, 4.75; N, 5.81; Cl, 7.90.

EXAMPLE 2 Alternate preparation of [(2-benzoyl-4-chlorophenylcarbamoyl)methyl]hydroxy carbamic acid, ethyl ester ethyl-carbonateReflux a mixture of 0.5 g. of5-chloro-2-hydroxyaminoacetamido-benzophenone and 15 ml. ofethylchloroformate for 3 hours. Remove the solvent under reducedpressure. Triturate the residue with a small amount of cold ethanol.Filter to obtain 0.15 g. of the title compound, M.P. 101-102".

EXAMPLE 3 Preparation of 7-chloro-l,3-dihydro-5-phenyl-2H1,4-benzodiazepin-2-one-3-carbamic acid, ethyl ester Add to a solution ofconcentrated ammonium hydroxide and ethanol, 300 mg. of[(2-benzoyl-4-chlorophenyl-carbamoyl)methyl]hydroxy carbamic acid, ethylester, ethyl carbonate. Heat to boiling to dissolve and concentrate to/2 of its original volume. Dilute with water, acidify with acetic acidand filter to remove solid impurities. Cool and filter to obtain thetitle compound, M.P. 253-255".

Analysis.Calculated for C H ClN O (percent): C, 60.42; H, 4.51; N,11.74; Cl, 9.91. Found (percent): C, 60.58; H, 4.21; N, 12,00; Cl, 9.90.

The subject matter which the applicant regards as his invention isparticularly pointed out and distinctly claimed as follows:

1. The process of preparing a[(Z-benzoylphenylcarbamoyDmethyl]hydroxycarbamic acid, ethyl ester,ethyl carbonate which comprises reacting a2-aminophenylbenzylideneaminoacetic acid N-oxide with ethylchloroformate.

2. The process of claim 1 wherein the2-aminophenylbenzylideneaminoacetic acid N-oxide is substituted withchlorine at the 5-position.

References Cited UNITED STATES PATENTS 3/1947 Bralley 26077.5 2/1966Hackman et al. 260-454 U.S. Cl. X.R.

